DESCRIPTION: (provided by the applicant) Microscopic Magnetic Resonance Imaging (uMRI) provides in vivo three-dimensional images of the mouse brain at high resolution (approximately 20 um) with exquisite soft tissue contrast. In this project we will combine Manganese Enhanced MRI (MEMRI) and Diffusion Tensor Imaging (DTI) to obtain precise maps of activated neuronal circuitry. Mn(2+) acts as an effective MRI contrast agent that it is taken up by active neurons, retained, and passed along neuronal circuitry trans-synaptically. Specific circuits can be probed using focal stereotaxic injections of Mn(2+) at different locations. Focal Mn(2+)-injection followed by an experimental protocol (physical, behavioral, pharmacological, etc.) performed with the awake "free running" animal, followed by MR imaging hours later will highlight neuronal circuitry passing near the site of injection that is activated by the protocol. DTI gives global maps of nerve fiber bundles, thus comparison with MEMRI furnishes the precise anatomical location of the active circuits. Our preliminary studies using small focal stereotaxic injections of Mn(2+) into the mouse brain and subsequent in vivo MR imaging show distinct and specific enhancement of neuronal tracts: injections into the amygdala yield MR enhancement in tracts to and through the hippocampus and onwards to the medial habenular nucleus. Diffusion Tensor Images at near microscopic resolution in rodents show exquisite detail of the anatomy of neuronal tracts. Work by Koretsky, Lin, and Pautler, as well as preliminary studies in this lab, confirm the feasibility of the MEMRI technique in highlighting active neuronal tracts in vivo. We are currently using DTI for anatomical mapping of fiber tracts in murine models of multiple model systems sclerosis. The goal of this project is to combine the two methodologies and demonstrate their effectiveness in two murine model systems: psychostimulant "addicted" mice and fear conditioned mice. The MEMRI/DTI method will be generally useful in all areas of neuroscience where one wants to know about the active neuronal circuitry associated with a particular murine model system. The MEMRI/DTI technique will supply a 3 dimensional image of active neuronal circuitry on the background of the fiber map of the brain.